2019 Research Project Descriptions
Below is an alphabetical list of Principal Investigators (PIs) and a description of the Summer Scholars research project they will be supervising. Please use the list to guide your selection of research projects in your application. Recall you can apply to as many as three projects but ONLY apply to locations to which you are willing (and eligible) to travel. During the final matching process, selected candidates will be offered an SRF Scholar position in a specific lab from among the list provided in the application. Do not forget to mention your specific interest in your choice(s) in your personal statement as well as an explanation of any relevant skills in your scientific statement.
Neurofibrillary tangles are a defining hallmark of both Alzheimer's and Parkinson's disease and they or similar aggregates also appear in the neuronal cytoplasm in other neurodegenerative diseases of old age. One possibility for their formation is that these tangles arise from an autophagic "traffic jam" caused by lysosomal inactivation. Lysosomal autophagy is an important mechanism by which cells rid themselves of such proteotoxic aggregates. Restoration of lysosomal function therefore constitutes an attractive candidate target for these disorders. As part of funded research from the SENS Foundation, we have established human tau P30L mutant versus wildtype-expressing neurons as an in vitro model of disease to test whether restoration of lysosomal function can prevent or reverse the formation of toxic tau aggregates. We determined using this model that low-dose (0.1 microM) application of a pharmacological accelerator of autophagic flux, K604, decreases levels of phosphorylated tau and protects against neurite retraction associated with the P30L model, even following their formation. We now propose to use this model to test newly identified lysosomal rejuvenating factors recently identified by our laboratory as part of a compound library screen for such compounds. These could potentially serve as novel therapeutics for the treatment of Alzheimer's and Parkinson's disease.
Mitochondria are the power plants of the cell and are also the only cellular organelle that possess their own DNA in mammals. In humans, mitochondrial DNA (mtDNA) codes for 13 important proteins, which all assemble into the oxidative phosphorylation relay. Mutations in mtDNA occur as a consequence of constant exposure to reactive oxygen species produced by the mitochondrial energy generation process as well as mistakes in mtDNA replication. These mutations accumulate over time due to inefficient repair mechanisms and compromise respiratory chain function. Inherited and acquired mutations in mtDNA result in impaired energy generation and are the cause for several pathologies such as Leber’s hereditary optic neuropathy (LHON), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Kearns-Sayre syndrome and Leigh syndrome.
At SENS Research Foundation, we are in the early stages of creating an exciting and innovative system to repair mitochondrial mutations. Using the allotopic approach, we have identified specific targeting elements/ sequences that can improve expression of these essential genes from the nuclear DNA and their transport to the correct location in mitochondria. The summer intern selected will get the opportunity to design and test a library of constructs in model patient cell lines with specific mutations to mtDNA. The ability of re-engineered genes to rescue function will be evaluated through various techniques, such protein gels, qPCR and activity assays, with the potential of extending the studies to animal models.
Cellular senescence is a basic aging process by which a cell undergoes a permanent arrest of cell division. Far from simple arrest, senescent cells are metabolically active – producing a vast array of secreted molecules that can drive pathology in the tissue microenvironment and potentially – systemically. Diabetes is a major risk factor for the development of several age-related degenerative conditions, including a form of kidney failure (diabetic nephropathy). Kidneys from diabetic patients and mice show accumulation of senescent cells – suggesting that senescence may drive kidney disease in response to diabetes. The Summer Scholar will work on a project to characterize the senescent state of kidney-derived proximal tubule epithelial cells (PTECs) in a tissue culture model. Key goals of this project include determining what pathways are activated by hyperglycemia that result in the senescence arrest; identifying and quantitating the factors secreted by these senescent cells; and assessing the effects of these secreted factors on other kidney cell types.
The potential project will involve modeling disease and aging in human induced pluripotent stem models. The Ellerby laboratory has established a number of disease models of Huntington’s disease, Parkinson’s disease and aging. We have developed different methods to identify novel therapeutic targets for HD and aging. The intern will generate models of disease and evaluate therapeutic targets to validate these for treatment of the disease.
As animals age they exhibit correlated recognizable and predictable changes to their physiology. These changes occur nearly synchronously across multiple tissues. Alterations in neuromodulatory signaling that lead to disruption of homeostasis may be one mechanism by which these concerted changes occur during aging. We want to understand how neuromodulators influence behavior and aging. Our lab develops new methods to monitor and manipulate signaling in living animals and to identify the fundamental enzymes that regulate inter-tissue communication. The goal of this project will be to characterize the role of intermediate filaments during aging in a C. elegans model.
Circadian rhythms are diurnal cycles of behavior (sleep/activity) and oscillations in cellular functions that are vital for maintaining homeostasis. Aging is accompanied by a gradual loss of circadian rhythm function and dampening in downstream rhythmic processes. Disruption of circadian clocks has been linked to accelerated aging and is a risk factor for several age-related diseases. Several studies show that disruption of circadian rhythms, genetically or through chronic jet-lag paradigms, is associated with neurodegeneration, obesity, and other age-related pathologies. However, the mechanisms by which circadian clocks influence aging and tissue homeostasis remain poorly understood.
The circadian system, similar to a free-swinging pendulum, maintains a rhythmic balance that slows over time as the animal ages. Our overall hypothesis is that dietary restriction (DR) slows aging by providing a push to the pendulum that increases the amplitude allowing the rhythmic motion to last longer. We base this on our previous findings showing that DR enhances circadian gene amplitude and that disruption of clocks abrogates the lifespan extension by DR. Similarly, in mice, high fat diet has been shown to dampen circadian rhythms, and circadian clocks are required for the lifespan extension upon calorie restriction. The goal of this lab is to understand the mechanisms by which DR enhances circadian amplitude and to identify the major clock output pathways that are important for tissue homeostasis and extending healthspan.
Approach: Our analysis of the DR circadian transcriptome revealed a significant enrichment for genes involved in the phototransduction cascade. Consistently, behavioral assays show that flies on DR show greater sensitivity to light. In this project, the Summer Scholar will test the hypothesis that DR enhances circadian amplitude by enhancing the light signals to the clock. Furthermore, the student will test whether DR delays the visual senescence observed in flies. We will use a combination of dietary and light manipulations in conjunction with genetic manipulations of the circadian clock and phototransduction genes in the fly eye to test their impact on circadian amplitude, visual senescence, and lifespan. Our experiments will address the importance of phototransduction in mediating some of the protective effects of DR.
Dr. Lithgow’s lab is focused on understanding the role of aging in the origins of age-related chronic disease. Specifically, his lab has led the field in the identification of pharmacological interventions in aging. The Lithgow lab utilizes molecular genetics, biochemistry and a range of leading edge technologies, including proteomics and metabolomics. His team utilizes the microscopic worm, C. elegans, which ages rapidly but exhibits many characteristics of human aging. Using this model, the lab has identified scores of chemical compounds that suppress disease phenotypes and extend lifespan. Many of these compounds promote protein homeostasis, which usually fails during normal aging and is also a factor in diseases such as Alzheimer’s and Parkinson’s.
Current Research Projects:
- Identifying chemical compounds (natural and synthetic) that promote proteostasis and extend healthspan and lifespan. The lab has identified scores of compounds with one or more of these properties and are working to understand their mechanisms of action. The lab is collaborating on mouse experiments testing the effects of these compounds on neurological disease and age-related bone loss.
- Determining the extent to which age-related accumulation of metals contribute to aging and disease pathology. We are manipulating metal levels in C. elegans using drug-like compounds.
- Investigating tissue-to-tissue signaling in the regulation of the mitochondria unfolded protein response.
- The lab is also part of a consortium, the Caenorhabditis Intervention Testing Program along with Monica Driscoll’s lab (Rutgers) and Patrick Phillips lab (Univ. of Oregon). The consortium is an NIA funded program to establish standard conditions for testing chemicals for effects on longevity and healthspan with a view to identifying robust interventions in aging for future pre-clinical and clinical research.
The Loring lab is focused on harnessing the power of pluripotent stem cells for regenerative medicine. We believe that cells derived from pluripotent stem cells will revolutionize medicine and lead to longer and healthier lives. We are looking for a Summer Scholar to work on our cell therapy project for Parkinson’s disease in which induced pluripotent stem cells from Parkinson’s patients are used to derive dopaminergic neurons, the same neurons which are lost in the brains of Parkinson’s patients. The aim of this Summer Scholar project is to evaluate whole-genome gene expression profiles from dopaminergic neurons derived from 10 different patient lines.
The Summer Scholar should have a strong interest in computational biology and ideally some background in computer science. The tools and skills for doing much of the bioinformatics analysis will be based around the Linux operating system. A working knowledge of Linux OS and some Python or R skills is desirable, along with an ability to solve data management problems independently and on-the-fly. Industry standard tools such as the GenomeAnalysisToolkit, Amazon AWS and Firecloud will be used to get an overview of the integrity of the neurons created in-house, and hence their suitability for transplantation.
This research project is geared toward performing translational research studying aging as it relates to the immune system and senescent cells. More specifically, the Summer Scholar will study how the immune system interacts with senescent cells. Research will include testing of candidate signaling protein blockers to try to induce killing of senescent cells. Another aspect of this project will involve identifying and characterizing new types of senescent cells from among the many tissue and cell types in the body. This will involve high-throughput microscopy on our robotic microscope. The research project will be a collaborative effort between SRF and the Buck Institute for Research on Aging, located in Novato, CA.
This project seeks to employ a small molecule approach to remove a toxic form of cholesterol from human blood in order to combat the development of atherosclerosis. Oxysterols are non-enzymatic cholesterol oxidation products that recently have become of interest in the pathology of several diseases, including atherosclerosis. The human body has difficulty processing such cholesterols and thus they accumulate in certain types of cells and tissues over time. We are testing the ability of various drugs to remove such toxic cholesterols from human cells. This rational drug design project will involve computational, in vitro, and ex vivo experiments and measurements of the activity of various compounds that we are testing. Our goal is to create a product based on SENS damage repair concepts that can be used in human patients in the near future.
Cell-based therapies are emerging as a promising strategy to tackle cancer. We have developed tumor cell surface receptor targeted T cells and adult stem cells expressing novel bi-functional pro-apoptotic and immunomodulatory proteins and oncolytic viruses. Using different primary and metastatic tumor models that mimic clinical settings, we show that that engineered stem cells expressing novel bi-functional proteins or loaded with oncolytic viruses target both the primary and the invasive tumor deposits and have profound anti-tumor effects. Recently, we have reverse engineered cancer cells using CRISPR/Cas9 technology and demonstrated self-tumor tropism and therapeutic potential of receptor self-targeted engineered cancer cells. These studies demonstrate the strength of employing engineered cells and real-time imaging of multiple events in preclinical-therapeutic tumor models and form the basis for developing novel cell based therapies for cancer.
We believe the study of stem cell biology will provide insights into many areas: developmental biology, homeostasis in the normal adult, and recovery from injury. Indeed, past and current research has already produced data in these areas that would have been difficult or impossible via any other vehicle. We have engaged in a multidisciplinary approach, simultaneously exploring the basic biology of stem cells, their role throughout the lifetime of an individual, as well as their therapeutic potential. Taken together, these bodies of knowledge will glean the greatest benefit for scientists and, most importantly, for patients. All of our research to date has been performed in animal models with the ultimate goal of bringing them to clinical trials as soon as possible.
Possible research project options include:
- Model Parkinson’s Disease (PD) using human induced pluripotent stem cells (hiPSCs)
- Search for molecules that confer a resistance to age-related degeneration
- What directs the homing of neural stem cells to areas of pathology?